This invention relates to gastrin and cholecystokinin (CCK) receptor ligands. The invention also relates to methods for preparing such ligands and to compounds which are useful intermediates in such methods. The invention further relates to pharmaceutical compositions comprising such ligands and methods for preparing such pharmaceutical compositions.
Gastrin and the cholecystokinins are structurally related neuropeptides which exist in gastrointestinal tissue and the central nervous system (Mutt V., Gastrointestinal Hormones, Glass G. B. J., ed., Raven Press, New York, p. 169; Nisson G., ibid., p. 127).
Gastrin is one of the three primary stimulants of gastric acid secretion. Several forms of gastrin are found including 34-, 17- and 14-amino acid species with the minimum active fragment being the C-terminal tetrapeptide (TrpMetAspPhe-NH2) which is reported in the literature to have full pharmacological activity (Tracey H. J. and Gregory R. A., Nature (London), 1964, 204, 935). Much effort has been devoted to the synthesis of analogues of this tetrapeptide (and the N-protected derivative Boc-TrpMetAspPhe-NH2) in an attempt to elucidate the relationship between structure and activity.
Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin. Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.
The cholecystokinins are reported to be important in the regulation of appetite. They stimulate intestinal mobility, gall bladder contraction, pancreatic enzyme secretion and are known to have a trophic action on the pancreas. They also inhibit gastric emptying and have various effects in the central nervous system.
Compounds which bind to cholecystokinin and/or gastrin receptors are important because of their potential pharmaceutical use as antagonists or partial agonists of the natural peptides.
A number of gastrin antagonists have been proposed for various therapeutic applications, including the prevention of gastrin-related disorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which lower gastrin activity or lower acid secretion is desirable. The hormone has also been shown to have a trophic action on cells and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach and the colon.
Possible therapeutic uses for cholecystokinin antagonists include the control of appetite disorders such as anorexia nervosa and the treatment of pancreatic inflammation, biliary tract disease and various psychiatric disorders. Other possible uses are in the potentiation of opiate (for example morphine) analgesia and in the treatment of cancers, especially of the pancreas. Moreover, ligands for cholecystokinin receptors in the brain (so-called CCKB receptors) have been claimed to possess anxiolytic activity.
According to the present invention, there are provided compounds of formula (I) 
wherein
X and Y are independently xe2x95x90Nxe2x80x94, xe2x80x94N(R5)xe2x80x94(R5 being selected from H, Me, Et, Pr, Bn, xe2x80x94OH and xe2x80x94CH2COOR6, wherein R6 represents H, Me, Et, Pr or Bn), xe2x95x90CHxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94;
n is from 1 to 4;
R1 is H or C1 to C15 hydrocarbyl wherein up to three C atoms may optionally be replaced by N, O and/or S atoms and up to three H atoms may optionally be replaced by halogen atoms;
R2 is selected from H, Me, Et, Pr and OH, each R2 being independently selected from H, Me, Et, Pr and OH when n is greater than 1;
R3 (when n is 1) is selected from H, Me, Et and Pr; or (when n is greater than 1) each R3 is independently selected from H, Me, Et and Pr, or two R3 groups on neighbouring carbon atoms are linked to form a C3 to C6 carbocylic ring, or two R3 groups are absent from neighbouring carbon atoms which are linked by a double bond; or R2 and R3 on the same carbon atom together represent an xe2x95x90O group;
R4 is C1 to C15 hydrocarbyl wherein up to two C atoms may optionally be replaced by N, O and/or S atoms and up to two H atoms may optionally be replaced by halogen atoms;
Z is xe2x80x94(NR7)axe2x80x94COxe2x80x94(NR8)bxe2x80x94 (wherein a is 0 or 1, b is 0 or 1, and R7 and R8 are independently selected from the groups recited above for R6), xe2x80x94COxe2x80x94NR7xe2x80x94CH2xe2x80x94COxe2x80x94NR8xe2x80x94, COxe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94NR8xe2x80x94 or a bond;
Q is xe2x80x94R9V, or 
(wherein R9 is xe2x80x94CH2xe2x80x94; xe2x80x94CH2xe2x80x94CH2xe2x80x94; or 
xe2x80x83or R9 and R8, together with the nitrogen atom to which R8 is attached, form a piperidine or pyrrolidine ring which is substituted by V;
V is xe2x80x94COxe2x80x94NHxe2x80x94SO2xe2x80x94Ph, xe2x80x94SO2xe2x80x94NHxe2x80x94COxe2x80x94Ph, xe2x80x94CH2OH, or a group of the formula xe2x80x94R10U, (wherein U is xe2x80x94COOH, tetrazolyl, xe2x80x94CONHOH or xe2x80x94SO3H; and
R10 is a bond; C1 to C6 hydrocarbylene, optionally substituted by hydroxy, amino or acetamido; xe2x80x94Oxe2x80x94(C1 to C3 alkylene)xe2x80x94; xe2x80x94SO2NR11xe2x80x94CHR12xe2x80x94;
xe2x80x94COxe2x80x94NR11xe2x80x94CHR12xe2x80x94, R11 and R12 being independently selected from H and methyl; or xe2x80x94NHxe2x80x94(CO)cxe2x80x94CH2xe2x80x94, c being 0 or 1);
T is C1 to C6 hydrocarbyl, xe2x80x94NR6R7 (wherein R6 and R7 are as defined above), xe2x80x94OMe, xe2x80x94OH, xe2x80x94CH2OH, halogen or trihalomethyl;
m is 1 or 2;
p is from 0 to 3; and
q is from 0 to 2, with the proviso that q is 1 or 2 when Z is a bond);
and pharmaceutically acceptable salts thereof.
In certain compounds according to the invention, R5 is selected from H, Me, Et, Pr and Bn; Z is xe2x80x94(NR7)axe2x80x94COxe2x80x94(NR8)bxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94CH2xe2x80x94COxe2x80x94NHxe2x80x94 or a bond; Q is 
V is xe2x80x94COxe2x80x94NHxe2x80x94SO2xe2x80x94Ph, xe2x80x94SO2xe2x80x94NHxe2x80x94COxe2x80x94Ph, xe2x80x94OCH2COOH, tetrazolyl or xe2x80x94CH2)sCOOH, wherein s is from 0 to 2; and T is C1 to C6 hydrocarbyl, xe2x80x94NR6R7, xe2x80x94OMe, xe2x80x94OH, xe2x80x94CH2OH or halogen. Such compounds are disclosed in U.K. patent application No. 9824536.8, the contents of which are hereby incorporated by reference.
A further group of compounds according to the invention are those in which R5 is selected from H, Me, Et, Pr and Bn; Z is xe2x80x94(NR7)axe2x80x94COxe2x80x94(NR8)bxe2x80x94, Q is xe2x80x94(CH2)rCOOH, wherein r is from 1 to 3; and T is C1 to C6 hydrocarbyl, xe2x80x94NR6R7, xe2x80x94OMe, xe2x80x94OH, xe2x80x94CH2OH or halogen.
A still further group of compounds according to the invention are those in which R5 is selected from H, Me, Et, Pr and Bn; xe2x80x94Zxe2x80x94Q is 
k is 1 or 2; and T is C1 to C6 hydrocarbyl, xe2x80x94NR6R7, xe2x80x94OMe, xe2x80x94OH, xe2x80x94CH2OH or halogen.
Preferably X and Y are independently xe2x95x90Nxe2x80x94, xe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NOHxe2x80x94, xe2x80x94NMexe2x80x94 or xe2x80x94NBnxe2x80x94. Most preferably X is xe2x80x94NHxe2x80x94 or xe2x80x94NOHxe2x80x94 and Y is xe2x95x90CHxe2x80x94 (or vice versa) or X is xe2x95x90Nxe2x80x94 and Y is xe2x80x94NHxe2x80x94 or xe2x80x94NOHxe2x80x94 (or vice versa).
Preferably R1 is C1 to C12 hydrocarbyl wherein one C atom may optionally be replaced by N or O and up to three H atoms may optionally be replaced by F, Cl or Br. More preferably R1 is C3 to C12 alicyclic; phenyl (optionally substituted with OMe, NMe2, CF3, Me, F, Cl, Br or I); or C1 to C8 alkyl. Alicyclic groups include C5 to C8 cycloalkyl, C7 to C10 polycycloalkyl, C5 to C8 cycloalkenyl and C7 to C10 polycycloalkenyl, all optionally substituted with methyl.
Preferably Z is xe2x80x94COxe2x80x94NHxe2x80x94.
Preferably Q is 
and more preferably 
p is preferably 0 or 1, and q is preferably 0. If p is greater than 0, then T is preferably C1 to C6 hydrocarbyl or halo.
m is preferably 1, and V is preferably xe2x80x94CO2H, xe2x80x94CH2CO2H or tetrazolyl.
Preferably R2 and R3 are H; n is 1 to 3; and R4 is C3 to C12 carbocyclic. More preferably, R4 is adamantyl, cycloheptyl, cyclohexyl or phenyl. Alternatively, R4 may be xe2x80x94NHxe2x80x94R13 or xe2x80x94OR13, wherein R13 is C3 to C12 carbocyclic, preferably adamantyl, cycloheptyl, cyclohexyl or phenyl.
R10 is preferably a bond, C1 or C2 alkylene (optionally substituted by hydroxy, amino or acetamido), xe2x80x94Oxe2x80x94(C1 to C3 alkylene)xe2x80x94; xe2x80x94SO2NR11xe2x80x94CHR12xe2x80x94; xe2x80x94COxe2x80x94NR11xe2x80x94CHR12xe2x80x94, xe2x80x94NHxe2x80x94(CO)cxe2x80x94CH2xe2x80x94, or a group of the formula 
Certain compounds of the invention exist in various regioisomeric, enantiomeric, tautomeric and diastereomeric forms. It will be understood that the invention comprehends the different regioisomers, enantiomers, tautomers and diastereomers in isolations from each other as well as mixtures.
Compounds of the invention wherein
(i) X is xe2x80x94NHxe2x80x94,
(ii) Y is xe2x95x90CHxe2x80x94, and
(iii) Z is xe2x80x94COxe2x80x94NHxe2x80x94
may conveniently be prepared by the route shown in Reaction Scheme A (in which PG represents a protecting group, and Qxe2x80x2 represents Q or a suitably protected derivative of Q): 
A suitably protected malonic acid derivative (II) is deprotonated and reacted with a suitably substituted acid chloride (III). The reaction product (IV) is deprotonated and reacted with a suitably substituted xcex1-bromo carbonyl compound (V). The reaction product (VI) is cyclised, using for example AcOH and AcONH4. The cyclisation product (VII) is deprotected to yield pyrrole (VIII). The free carboxylic acid of pyrrole (VIII) is activated, using for example SOCl2, and reacted with a suitably substituted amine (IX) to yield compound (X). Any appropriate deprotection carried out on compounds (X) leads to compounds of the invention wherein X is xe2x80x94NHxe2x80x94, Y is xe2x95x90CHxe2x80x94 and Z is xe2x80x94COxe2x80x94NHxe2x80x94.
Compounds of the invention wherein
(i) X is xe2x80x94NHxe2x80x94 and Y is xe2x95x90Nxe2x80x94, or X is xe2x95x90Nxe2x80x94 and Y is xe2x80x94NHxe2x80x94, and
(ii) Z is xe2x80x94COxe2x80x94NR8xe2x80x94
may conveniently be prepared by the route shown in reaction Scheme B (in which Qxe2x80x2 and PG are as defined above): 
A suitably substituted carboxylic acid (XI) is reacted, using for example EDC or SOCl2, with a suitably protected phosphorous ylid (XII). The product ylid (XIII) is oxidised, using for example oxone. The oxidation product (XIV) is cyclised with a suitably substituted aldehyde (XV), using for example AcOH and AcONH4. The cyclisation product (XVI) is deprotected to yield imidazole (XVII). The free carboxylic acid of imidazole (XVII) is activated, using for example PyBrOP or EDC, and reacted with a suitably substituted amine (XVIII) to yield compound (XIX). Any appropriate deprotection carried out on compounds (XIX) leads to compounds of the invention wherein X is xe2x80x94NHxe2x80x94 and Y is xe2x95x90Nxe2x80x94 or X is xe2x95x90Nxe2x80x94 and Y is xe2x80x94NHxe2x80x94, and Z is xe2x80x94COxe2x80x94NHxe2x80x94.
Compounds in which X is xe2x80x94NR5xe2x80x94 (wherein R5 is alkyl) may be made by treatment of compound (XVI) with sodium hydride, followed by quenching with R5Br, activation, reaction with Qxe2x80x2NHR8 and deprotection (if appropriate).
Hence another aspect of the present invention is a method of making a compound of formula (I). Preferably said method includes the step of cyclising a suitable precursor (VI) or (XIV) to yield a five membered ring, preferably a pyrrole (VII) or an imidazole (XVI). Preferably said cyclisation is effected using AcOH and AcONH4. The invention further provides compounds which are useful intermediates in such methods.
Compounds of the invention wherein Z is xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94 may conveniently be prepared by the route shown in reaction Scheme C, in which Qxe2x80x2 is as defined above. Xxe2x80x2 and Yxe2x80x2 correspond to X and Y, except that when X (or Y) is xe2x80x94NHxe2x80x94, Xxe2x80x2 (or Yxe2x80x2, as the case may be) is xe2x80x94N(PG)xe2x80x94, in which PG represents a protecting group. 
In this reaction scheme, the starting compound (XX) may be, for example, an Nxe2x80x94 protected derivative of compound (XVII) shown in Reaction Scheme B. Compound (XX) is first treated with ethylchloroformate and triethylamine, and sodium azide is then added. After heating under reflux, the compound (XXI) is obtained. Reaction of this compound with an amine of the formula Qxe2x80x2xe2x80x94NH, followed by appropriate deprotection, yields the urea derivative (XXII). Alternatively, compound (XXI) may be reacted with benzyl alcohol, followed by catalytic hydrogenation (using, for example, a Pd/C catalyst) to yield the corresponding amine (XXIII). This, in turn, may be reacted with an acid chloride of the formula Qxe2x80x2xe2x80x94COCl, followed by appropriate deprotection, to provide the xe2x80x9creversexe2x80x9d amide (XXIV).
Compounds wherein Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 may conveniently be prepared by the method shown in Reaction Scheme D. In this scheme, compound (XXV) is an ester derived, for example, from compound (VII) shown in Reaction Scheme A or compound (XVI) shown in Reaction Scheme B. It is first reduced to the corresponding alcohol, such as by reaction with lithium aluminium hydride, followed by oxidation (e.g. using manganese(IV) oxide) to form the corresponding aldehyde (XXVI). The aldehyde, in turn, is reacted with a triphenylphosphonium compound of the formula Qxe2x80x2xe2x80x94CH2xe2x80x94PPh3+Brxe2x88x92, to yield compound (XXVII). This may be deprotected as required to yield the target compound (XVIII) in which Z is xe2x80x94CHxe2x95x90CHxe2x80x94, or it may first be reduced and then deprotected (as necessary) to provide the compound (XXIX) in which Z is xe2x80x94CH2xe2x80x94CH2xe2x80x94. 
Compounds wherein X is xe2x95x90Nxe2x80x94 and Y is xe2x80x94Sxe2x80x94 may be prepared by the procedure outlined in Reaction Scheme E. 
Compound (IV) (Reaction Scheme A) is first reacted with sulfonyl chloride to form compound (XXX), which is then refluxed in a suitable solvent (such as ethanol) with a compound of formula R1xe2x80x94CSxe2x80x94NH2, leading to formation of the thiazole derivative (XXXI). This is then deprotected to form the corresponding carboxylic acid (XXXII), the carboxyl group of which may then be elaborated as shown in Reaction Schemes A, B and C. For example, amidation with a suitably protected amine Qxe2x80x2xe2x80x94NH2 leads to compound (XXXIII), which may then be deprotected to yield the target compound. The amidation reaction is preferably carried out using PyBrOP and N,N-diisopropylethylamine.
Compounds wherein X is xe2x80x94Sxe2x80x94 and Y is xe2x95x90Nxe2x80x94 may be prepared by the method illustrated in Reaction Scheme F. 
Compound (XXXIV), which may be prepared by the general methodology of Example 120, step a, is reacted with Lawesson""s reagent to form the protected thiazole derivative (XXXV). This may then be deprotected, and the carboxyl group subsequently elaborated as described above.
Compound (XXXIV) may also be used in the preparation of compounds in which X is xe2x80x94Oxe2x80x94 and Y is xe2x95x90Nxe2x80x94, as shown in Reaction Scheme G. 
In this case, carbon tetrachloride, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and triphenylphosphine are sequentially added to a solution of compound (XXXIV) to form the protected oxazole derivative (XXXVI). This may then be deprotected, and the carboxyl group subsequently elaborated in the same way as for the corresponding imidazole, pyrrole and thiazole compounds.
Compounds of the invention wherein
(i) X is xe2x80x94Nxe2x95x90,
(ii) Y is xe2x80x94N(OH)xe2x80x94, and
(iii) Z is xe2x80x94COxe2x80x94NR8xe2x80x94
may conveniently be prepared by the route shown in Reaction Scheme H 
The dioxane-dione derivative (XXXVII) may be obtained by reaction of the corresponding acid R4xe2x80x94(CR2R3)nxe2x80x94COOH with carbonyl di-imidazole, as illustrated in Example 308 below. Compound (XXXVII) is then reacted with amine Qxe2x80x2NHR8, such as by heating in toluene in the presence of catalytic quantities of DMAP. The product (XXXVIII) is reacted with sodium nitrite to form the hydroxyimino derivative (XXXIX). This is then reacted with the aldehyde R1CHO to form the substituted hydroxyimidazole (XL), which is subsequently deprotected as appropriate.
The protected hydroxyimidazole (XL) provides a further route to the corresponding imidazole compound (XLII), by treatment with trimethylphosphite, and subsequent deprotection (if necessary).
An alternative way of making intermediates which may be elaborated to compounds of the invention in which X is xe2x80x94Nxe2x95x90 and Y is xe2x80x94NR5 (or vice versa) is shown in Reaction Scheme I. The protected carboxyl group of compound (XLV) may be deprotected in conventional manner, and the free carboxyl group may then be elaborated in the ways discussed above. Alternatively, compound (XLV) may be converted to compound (XVI) by reaction with trimethylphosphite. 
Still further routes to compound (XVI) are illustrated in Reaction Scheme J and Reaction Scheme K below. 
In these reaction schemes, the final product is the compound (XVI) having a protected carboxyl group. This may be deprotected and subsequently elaborated to provide compounds according to the invention, as discussed above.
The invention also comprehends derivative compounds (xe2x80x9cpro-drugsxe2x80x9d) which are degraded in vivo to yield the species of formula (I). Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded. Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion of pro-drugs may be found in Stella, V. J. et al., xe2x80x9cProdrugsxe2x80x9d, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.
Pro-drug forms of the pharmacologically-active compounds of the invention will generally be compounds according to formula (I) having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the form xe2x80x94COOR14, wherein R14 is C1 to C5 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or one of the following: 
Amidated acid groups include groups of the formula xe2x80x94CONR15R16, wherein R15 is H, C1 to C5 alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl, and R16 is xe2x80x94OH or one of the groups just recited for R15.
Compounds of formula (I) having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This will hydrolyse with first order kinetics in aqueous solution.
Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) substantially as described herein before with a pharmaceutically acceptable diluent or carrier.
Yet another aspect of the present invention is a method of making a pharmaceutical composition comprising a compound of formula (I) substantially as described herein before, comprising mixing said compound with a pharmaceutically acceptable diluent or carrier.
Pharmaceutically acceptable salts of the acidic or basic compounds of the invention can of course be made by conventional procedures, such as by reacting the free base or acid with at least a stoichiometric amount of the desired salt-forming acid or base.
Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with inorganic cations such as sodium, potassium, calcium, magnesium, and zinc, and salts with organic bases. Suitable organic bases include N-methyl-D-glucamine, arginine, benzathine, diolamine, olamine, procaine and tromethamine.
Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable anions include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride. iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate and triethiodide.
It is anticipated that the compounds of the invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and inhalation.
For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatine capsules in which the active ingredient Is mixed with a solid diluent and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer""s solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
Effective doses of the compounds of the present invention may be ascertained be conventional methods. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration and the weight of the patient. In general, however, it is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.001 to 5000 mg per day, more usually from 1 to 1000 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.01 xcexcg/kg and 50 mg/kg, especially between 10 xcexcg/kg and 10 mg/kg, eg. between 100 xcexcg/kg and 2 mg/kg.
The term xe2x80x9chydrocarbylxe2x80x9d is used herein to refer to monovalent groups consisting of carbon and hydrogen. Hydrocarbyl groups thus include alkyl, alkenyl and alkynyl groups (in both straight and branched chain forms), cycloalkyl (including polycycloalkyl), cycloalkenyl and aryl groups, and combinations of the foregoing, such as alkylcycloalkyl, alkylpolycycloalkyl, alkylaryl, alkenylaryl, alkynylaryl, cycloalkylaryl and cycloalkenylaryl groups.
A xe2x80x9ccarbocyclicxe2x80x9d group, as the term is used herein, comprises one or more closed chains or rings, which consist entirely of carbon atoms. Carbocyclic groups thus include aryl groups (such as phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl, and substituted derivatives thereof), and also alicyclic groups. The term xe2x80x9calicyclic groupxe2x80x9d refers to a carbocyclic group which does not contain an aromatic ring, and thus includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, norbornyl, bicyclo[2.2.2]octyl, norbornyl and bicyclo[2.2.2]octenyl, and also groups (such as adamantanemethyl and methylcyclohexyl) which contain both alkyl or alkenyl groups in addition to cycloalkyl or cycloalkenyl moieties.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight and branched chain forms.
A xe2x80x9cheterocyclicxe2x80x9d group comprises one or more closed chains or rings which have at least one atom other than carbon in the closed chain or ring. Examples include benzimidazolyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl.
When reference is made herein to a substituted carbocyclic group (such as substituted phenyl) or a substituted heterocyclic group, the substituents are preferably from 1 to 3 in number and selected from C1 to C6 alkyl, C1 to C6 alkoxy, thio, C1 to C6 alkylthio, carboxy, carboxy (C1 to C6)alkyl, formyl, C1 to C6 alkylcarbonyl, C1 to C6 alkylcarbonylalkoxy, nitro, trihalomethyl, hydroxy, C1 to C6 alkylhydroxy, hydroxy(C1 to C6)alkyl, amino, C1 to C6 alkylamino, di(C1 to C6 alkyl)amino, aminocarboxy, C1 to C6 alkylaminocarboxy, di(C1 to C6 alkyl)aminocarboxy, aminocarboxy(C1 to C6)alkyl, C1 to C6 alkylaminocarboxy(C1 to C6)alkyl, di(C1 to C6 alkyl)aminocarboxy(C1 to C6)alkyl, C1 to C6 alkylcarbonylamino, C5 to C8 cycloalkyl, C5 to C8 cycloalkyl(C1 to C6)alkyl, C1 to C6 alkylcarbonyl(C1 to C6 alkyl)amino, aryl, aryl(C1 to C6)alkyl, (C1 to C6 alkyl)aryl, halo, C1 to C6 alkylhalo, sulphamoyl, tetrazolyl and cyano.
The term xe2x80x9chalogenxe2x80x9d is used herein to refer to any of fluorine, chlorine, bromine and iodine. Most usually, however, halogen substituents in the compounds of the invention are chlorine and fluorine substituents.